Treatment Patterns and Attrition With Lines of Therapy for Advanced Urothelial Carcinoma in the US

Key Points Question What are the current treatment patterns and attrition rates in patients with advanced urothelial cancer? Findings In this cohort study of 7260 patients with advanced urothelial cancer who received first-line treatment, only 2714 (37%) progressed to second-line treatment, and 857 (12%) reached third-line treatment. The most common first-line regimens were carboplatin and programmed cell death 1 and/or programmed cell death ligand 1 inhibitors; novel therapeutic agents like enfortumab vedotin, sacituzumab govitecan, and erdafitinib have increased adoption after 2019. Meaning The attrition rates observed in this study emphasize the necessity for more effective and tolerable front-line treatment options for patients with advanced urothelial cancer.


Introduction
An estimated 82 290 new cases and 16 710 deaths are projected to be attributable to bladder cancer in the US in 2023. 1 Although the 5-year survival rate for localized bladder cancer is 71%, the rate drops significantly to 8.3% for metastatic bladder cancer. 2Urothelial (transitional cell) carcinomas are the most common histological subtype of bladder cancer. 3The treatment landscape of urothelial cancer has evolved significantly over the past few years.5][6] Carboplatin with gemcitabine remains a viable front-line treatment choice for patients with aUC deemed ineligible for cisplatin-based therapy. 7Several programmed cell death 1 and/or programmed cell death ligand 1 (PD-1/PD-L1) inhibitors are approved for use in aUC.
10][11] Pembrolizumab is also approved for use in the first-line setting for patients with aUC ineligible for any platinum-containing chemotherapy. 8,12Avelumab is approved for maintenance therapy for patients with aUC whose disease has not progressed following initial platinum-based treatment. 8,13e pan-fibroblast growth factor receptor (FGFR) inhibitor erdafitinib has been granted accelerated approval for patients with aUC with susceptible FGFR2 or FGFR3 genetic alterations and whose disease has progressed during or following platinum-based therapy. 8,14Enfortumab vedotin is a nectin-4-directed antibody and microtubule inhibitor conjugate approved for use in aUC. 8,15,16cituzumab govitecan, another antibody-drug conjugate consisting of a monoclonal antibody targeting trophoblast-antigen-2 linked to the active metabolite of irinotecan (SN-38), has received accelerated approval for the treatment of patients with aUC who have previously undergone platinum-based chemotherapy and PD-1/PD-L1 inhibitor treatment. 8,17eatment patterns outside clinical trials are likely to exhibit variations compared with those observed in the clinical trial population.Clinical trials frequently include patients with more favorable prognoses, which can complicate the generalizability of treatment patterns to a broader and more diverse patient population. 18Data derived from a patient population outside a clinical trial may serve as a valuable adjunct to the knowledge accrued through clinical trials, which could significantly affect patient care and contribute to advances in therapeutic development. 19,20In this study, we used a nationwide, deidentified database to evaluate the treatment patterns and attrition rates in patients with aUC in oncology clinics across the US.

Methods
This cohort study was approved by the Institutional Review Board at the University of Utah (a National Cancer Institute-Comprehensive Cancer Center), which did not require informed consent owing to the use of deidentified data, and fully complied with the US patient confidentiality regulations, including adherence to the Health Insurance Portability and Accountability Act of 1996.
The study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Study Design
We conducted a retrospective cohort study with extracted patient data from the Flatiron Health electronic health record-derived database. 19,21The longitudinal Flatiron Health database is composed of deidentified patient-level structured and unstructured data and curated via technology-enabled abstraction. 22,23During the study period, the deidentified data originated from approximately 280 oncology clinics (around 800 sites of care) across the US. 21,24Most patients in the database originate from community oncology settings; relative proportions of community to academic settings may vary depending on the study cohort.The electronic health record data are subjected to anonymization procedures and encompass structured data such as cancer-related diagnoses, disease staging, medication records, and abstracted information extracted from unstructured sources, notably physicians' clinical notes.

Patient Population
Patients were eligible to be included in the study if they had a diagnosis consistent with aUC.Patients who did not receive first-line therapy, who received treatment for 2 or more cancers, or who were participating in clinical trials in any line of therapy were excluded.In our analytic cohort, patients received treatment for aUC at the participating site from January

Statistical Analysis
Treatments in each line of therapy were summarized using frequency and percentages.All analyses were performed using R, version 4.2.3 (R Project for Statistical Computing).

Results
Of the 12 157 patients included from the database with aUC, 8660 had information on lines of therapy.After excluding patients who received treatment for 2 or more cancers or were enrolled in clinical trials, 7260 patients were included in the final analysis cohort (5364 [73.9%] men and 1894 [26.1%] women, with data missing for 2; median age at the start of first-line treatment, 73 [IQR, 66-80] years) (eFigure 1 in Supplement 1).With regard to race and ethnicity distribution, 282 participants (3.9%) were Hispanic or Latino, 84 (1.2%) were non-Hispanic Asian, 319 (4.4%) were non-Hispanic Black, 4957 (68.3%) were non-Hispanic White, 910 (12.5%) were of other race or ethnicity, and 708 (9.8%) were of unknown race or ethnicity.The focus was not on disparities but on significant attrition rates.
Of the patients in the analysis cohort, 7260 received 1 line of therapy, 2714 (37.4%) received 2 lines, and 857 (11.8%) received 3 or more lines.A breakdown of the first 6 lines of therapy is presented in the Table .Most patients who received PD-1/PD-L1 inhibitor therapy in the first line of treatment did not receive any further lines.eFigure 2 in Supplement 1 depicts the percentage of patients with aUC receiving first, second, and third lines of therapy.Figure 1 shows the treatment sequencing by lines of therapy.
A subanalysis was conducted to assess attrition rates over time.The cohort was divided into patients who started first-line therapy between January 1, 2011, and May 17, 2016, and those who began first-line therapy between May 18, 2016, and January 31, 2023.The point of May 18, 2016, was chosen due to the approval of atezolizumab by the US Food and Drug Administration (FDA) on this date, and the approval of newer, better-tolerated therapies could potentially affect the attrition rates.In the first group (January 1, 2011, to May 17, 2016), 2166 patients received a first line of therapy; of those patients, 795 (36.7%) received a second line and 257 (11.9%) received a third line of therapy.In the second group (May 18, 2016, to January 31, 2023), 5094 received a first line of therapy; of those patients, 1919 (37.7%) received a second line and 600 (11.8%) received a third line of therapy.

Treatment Landscape in the First-Line Setting
In the first-line setting, carboplatin was the most commonly used regimen (2241 [30.9%]), followed  Abbreviation: PD-1/PD-L1, programmed cell death 1 and/or programmed cell death ligand 1.

Discussion
Using the Flatiron Health database, we evaluated treatment patterns and attrition rates in aUC from 2011 to 2023.Carboplatin-based regimens are the most commonly used in first-line treatment, although there has been a gradual increase in the use of PD-1/PD-L1 inhibitor therapy since 2016.
Therapy with PD-1/PD-L1 inhibitors is the predominant choice in second and third lines.The adoption of novel therapies has gradually increased in the second and third lines.An alarmingly high attrition rate was observed in the cohort, with only 37.4% receiving 2 or more lines of treatment and merely 11.8% receiving 3 or more.
In first-line treatment, carboplatin emerged as the most frequently used therapeutic regimen.
Notably, while cisplatin represents a current standard of care for first-line treatment for aUC among eligible patients, carboplatin serves as an acceptable alternative for patients ineligible for cisplatinbased therapy.Galsky et al 25 conducted a meta-analysis of 4 randomized trials, [26][27][28][29] revealing that cisplatin-based regimens have better response rates than carboplatin-containing regimens.Prior studies 19,[30][31][32][33] have indicated a notably increased use of carboplatin in first-line treatment.This can be a result of cisplatin ineligibility in most patients and concerns for cisplatin toxicity in an elderly population with comorbidities and a lack of social support. 33e use of PD-1/PD-L1 inhibitor therapy in the first line began increasing in 2016, with a notably substantial rise observed in 2017.In 2017, the US FDA granted accelerated approval to first-line atezolizumab for patients with aUC who were ineligible for cisplatin, based on the results of cohort 1   of the phase 2 IMvigor210 study. 8,34In parallel, in 2017, pembrolizumab was granted accelerated approval for the same indication based on the phase 2 KEYNOTE-052 trial results. 8,35In 2018, the FDA issued a safety advisory concerning the use of pembrolizumab and atezolizumab as monotherapy in first-line treatment.This advisory was prompted by preliminary analyses of data from 2 ongoing clinical trials, specifically the KEYNOTE-361 and IMvigor130 trials, which revealed decreased overall survival among patients administered pembrolizumab or atezolizumab compared with those who received cisplatin-or carboplatin-based therapeutic regimens. 12,36Subsequently, based on data from these trials, the indication for pembrolizumab was amended to its current form, and the manufacturers of atezolizumab voluntarily withdrew its indication in first-line treatment of aUC in 2022. 8Avelumab, approved in 2020 for maintenance therapy in aUC, likely also contributes to a proportion of PD-1/PD-L1 inhibitors used in our study. 8,13 second-line treatment, PD-1/PD-L1 inhibitor therapy was the most commonly used regimen.

JAMA Network Open | Oncology
Between 2011 and 2015, platinum-based therapy and single-agent nonplatinum chemotherapy predominated.However, a notable shift occurred in 2016, marked by a pronounced increase in the adoption of PD-1/PD-L1 inhibitors.In 2016, atezolizumab received accelerated approval for the treatment of patients with aUC who had experienced disease progression after or during platinumbased chemotherapy, based on the outcomes of cohort 2 within the phase 2 IMvigor210 trial. 8,37This approval, coupled with the favorable safety profile of atezolizumab and patient perception, likely contributed to the heightened adoption of this approach. 37,38Following atezolizumab's approval, nivolumab and avelumab also received accelerated approvals, while pembrolizumab was granted regular approval in 2017 for the same indication as atezolizumab. 8However, in 2021, the manufacturers of atezolizumab voluntarily withdrew its indication for use in aUC postplatinum therapy based on the results of the phase 3 IMvigor211 trial that failed to show a survival benefit with atezolizumab compared with single-agent chemotherapy. 8,39The use of erdafitinib displayed a notable upswing in 2019, concomitant with the accelerated approval of erdafitinib in the same year. 8fortumab vedotin received accelerated approval in December 2019 for the treatment of patients with aUC who had previously undergone platinum-based chemotherapy and PD-1/PD-L1 inhibitor therapy, predicated on the results of the phase 2 EV-201 trial. 8,40The approval corresponded to increased use, as shown in Figure 3 .In 2021, the FDA expanded the approved indication for enfortumab vedotin in aUC to encompass patients who were ineligible for cisplatin and had experienced disease progression following at least 1 line of therapy. 8Use of sacituzumab govitecan increased in 2021, in alignment with its accelerated approval in the same year. 8Notably, we also noticed a decline in the use of erdafitinib with the increasing use of enfortumab vedotin and sacituzumab govitecan.The observations in third-line treatment mirrored those in the second line, wherein PD-1/PD-L1 inhibitors remained the predominant choice, and a discernible rise in the use of novel therapeutic agents commenced in 2019.
One of the most startling findings in our study pertained to the elevated attrition rates, wherein merely 37.4% of patients received a minimum of 2 lines of therapy, and 11.8% received at least 3 lines.
Our subanalysis found similar attrition rates in patients starting first-line treatment for aUC from January 1, 2011, to May 17, 2016, and those starting first-line treatment from May 18, 2016, to January 31, 2023.These high attrition rates align with findings from prior studies on aUC. 18,19,30,33Multiple factors may contribute to these high attrition rates, including socioeconomic variables, difficulties in accessing affordable health care, and the use of treatment regimens characterized by poor tolerability and modest efficacy. 33A promising strategy for optimizing patient treatment is the implementation of front-line therapeutic regimens known for their effectiveness and favorable tolerability profiles.The phase 3 EV-302-KEYNOTE-A39 trial 41 exemplifies such an approach, where the combination of enfortumab vedotin and pembrolizumab was compared with gemcitabine plus platinum chemotherapy for previously untreated locally advanced or metastatic urothelial carcinoma.The results of the trial showed a significant improvement in progression-free survival  41 These compelling results are anticipated to position the combination of enfortumab vedotin and pembrolizumab as the new standard of care in first-line treatment of aUC at the potential expense of platinum-based chemotherapy.Nevertheless, it remains uncertain whether enfortumab vedotin with pembrolizumab is the optimal choice for patients who have undergone prior anti-PD-1 therapy in the adjuvant setting.Makrakis et al 42 conducted a retrospective study revealing that patients receiving a second immune checkpoint inhibitor (ICI) after progression during initial ICI treatment demonstrated an overall response rate of 13%.This finding implies that a limited subset of patients rechallenged with an ICI may experience clinical benefits, but whether enfortumab vedotin with pembrolizumab will provide additional benefit compared with single-agent enfortumab needs to be explored.Clinical trials are essential to address this crucial question. 42For patients for whom enfortumab vedotin with pembrolizumab is not a viable option, an alternative choice is nivolumab in combination with gemcitabine and cisplatin.
CheckMate 901, 43 a phase 3 trial, compared nivolumab plus gemcitabine and cisplatin with gemcitabine and cisplatin alone.Adding nivolumab produced a statistically significant increase in the median PFS (7.9 [95% CI, 7.6-9.5]vs 7. ).In the nivolumab group, 62% experienced grade 3 or higher adverse effects, compared with 52% in the gemcitabine plus cisplatin group. 43The ongoing NILE trial 44  Even with these advances, attrition rates may continue to be high, and a comprehensive, patient-centric approach needs to be made to make a difference.This will not only entail bringing effective and well-tolerated therapies at reasonable cost in earlier disease settings but also improving social support and use of novel ways through information and technology to deliver patient care near their residence.
by PD-1/PD-L1 inhibitors (2174[29.9%])and cisplatin-based regimens (2008[27.7%]).eFigure 3 in Supplement 1 displays the frequency of different regimens in the first-line setting.Use of platinum-based chemotherapy declined starting in 2016, with a corresponding increase in PD-1/PD-L1 inhibitor therapy in the first line.These changes plateaued around 2018.Figure2shows the patterns of first-line treatment for aUC from 2011 to 2023.Treatment Landscape in the Second-Line SettingTherapy consisting of PD-1/PD-L1 inhibitors was the most commonly used in the second line (1412[52.0%]),followed by carboplatin (403 [14.8%]) and single-agent nonplatinum chemotherapy (342 [12.6%]).eFigure 4 in Supplement 1 displays the frequency of regimens used in the second-line setting.The uptake of PD-1/PD-L1 inhibitor therapy increased starting in 2016 compared with previous years, with a corresponding decrease in the use of platinum-based chemotherapy.Since 2019, a consistent rise in the use of novel agents like enfortumab vedotin (219 [8.1%]), erdafitinib (39 [1.4%]), and sacituzumab govitecan (14 [0.5%]) occurred.Figure 3 shows the patterns of secondline treatment for aUC from 2011 to 2023.Treatment Landscape in the Third-Line Setting Therapy based on PD-1/PD-L1 inhibitors represented the predominant third-line treatment regimen (258 [30.1%]), followed by single-agent nonplatinum chemotherapy (169 [19.7%]) and novel agent enfortumab vedotin (159 [18.6%]).eFigure 5 in Supplement 1 displays the frequency of use of each regimen in the third-line setting.The use of platinum chemotherapy decreased with a corresponding increase in PD-1/PD-L1 inhibitor therapy from 2015.Since 2019, a consistent increase in the use of novel therapies has occurred, similar to the second-line setting, including enfortumab vedotin as noted above, erdafitinib (28 [3.3%]), and sacituzumab govitecan (34 [4.0%]).Figure 4 shows the patterns of third-line treatment for aUC from 2011 to 2023.

Figure 1 .
Figure 1.First-to Third-Line Treatment Patterns for Advanced Urothelial Cancer

Figure 4 .PD- 1 /
Figure 4. Third-Line Treatment Patterns for Advanced Urothelial Cancer From 2011 to 2023 100 is evaluating durvalumab with or without tremelimumab in combination with platinum-based chemotherapy as first-line treatment for locally advanced unresectable and metastatic urothelial cancer.Future trials incorporating predictive biomarkers for guiding treatment selection could potentially refine treatment choices in patients with aUC.

eFigure 2 . 3 . 4 . 5 .
Illustration of Patients With Advanced Urothelial Carcinoma Receiving First, Second, and Third Lines of Therapy eFigure Frequency of Use of Different Regimens in the First-Line Setting eFigure Frequency of Use of Different Regimens in the Second-Line Setting eFigure Frequency of Use of Different Regimens in the Third-Line Setting 1, 2011, to January 31, 2023.